Age-related macular degeneration (AMD) is the most common cause of legal blindness in the US. There is no effective treatment for the most prevalent dry form of AMD. Dry AMD is triggered by abnormalities in the retinal pigment epithelium (RPE) which induce secondary degeneration of photoreceptors in the central part of the retina called macula. Excessive accumulation of lipofuscin granules in RPE is thought to cause degeneration of RPE and adjacent photoreceptors in AMD retinas. The major cytotoxic component of RPE lipofuscin is a pyridinium bisretinoid A2E which is formed as a by-product of a properly functioning visual cycle. It was suggested that visual cycle inhibitors may reduce the formation of A2E/lipofuscin and prolong RPE and photoreceptor survival in AMD. Rates of the visual cycle and A2E production depend on the influx of all-trans retinol from serum to the RPE. Formation of the tertiary retinol-binding protein (RBP)- transthyretin (TTR)-retinol complex is required for retinol uptake from serum to the RPE. Non-toxic compounds that compete with serum retinol for binding to RBP while blocking the RBP-TTR interaction would reduce serum retinol, slow down the visual cycle, and inhibit A2E synthesis. The studies outlined in this proposal seek to develop an HTRF assay for antagonists of retinol-induced RBP-TTR interaction (Specific Aim 1) and to adapt this assay to the HTS format suitable for screening of a compound collection at one of the NIH MLSCN screening centers (Specific Aim 2). PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the most common cause of legal blindness in the US;there is no effective treatment for the most prevalent atrophic (dry) form of AMD. We propose to develop a high-throughput screen for small molecule visual cycle inhibitors that may become a new treatment for atrophic AMD and for other forms of retinal degeneration in humans.